Single letter of DNA 'defines hair color'

Changing just one letter of genetic code is enough to generate blonde hair in humans, according to a new analysis from researchers at the Howard Hughes Medical Institute in Chevy Chase, MD.

David Kingsley, of the Howard Hughes Medical Institute, has been studying the evolution of sticklebacks - the small fish that moved from the seas to colonize lakes and streams at the end of the last Ice Age - for the last 10 years.

Using the sticklebacks' adaptive responses to different habitats as a case study, Kingsley and his colleagues have been able to identify molecular-level changes responsible for driving evolution. More recently, they have turned their attention to see how evolutions in the stickleback might apply to other species, such as humans.

The research that led Kingsley's team to investigate the genetic code responsible for hair color initially concerned changes in stickleback pigmentation. As part of a 2007 study, they found that a change in the same gene had driven pigmentation changes in different populations of sticklebacks around the world.

Interestingly, they found that this genetic change was not unique to the stickleback.

Same gene in sticklebacks and humans controls pigmentation

"The very same gene that we found controlling skin color in fish showed one of the strongest signatures of selection in different human populations around the world," Kingsley says.

The genome "is littered with switches," the researchers suspect.

Different versions of this gene - called "Kit ligand" - in humans are associated with differences in skin color. In both fish and humans, Kingsley found, the genetic changes thought to be responsible for pigmentation differences take place in regulatory elements of the genome.

"It looked like regulatory mutations in both fish and humans were changing pigment," Kingsley says.

But tracking down specific regulatory elements in the whole genome is like finding a needle in the proverbial haystack. "We have to be kind of choosy about which regulatory elements we decide to zoom in on," Kingsley acknowledges.

As well as encoding a protein that develops pigment-producing cells, however, Kit ligand has many other functions. For example, it influences the behaviors of blood stem cells, sperm or egg precursors and neurons in the intestine.

The team was interested in seeing whether they could isolate the regulatory changes in Kit ligand responsible for hair color without affecting any of the gene's other functions.

'Switching on' Kit ligand's hair color-determining powers

To do this, a research specialist in Kingsley's team - Catherine Guenther - cut out segments of human DNA in the implicated region and linked each piece to a reporter gene. When these genes correctly "switch on," they produce a distinctive blue color.

Next, Guenther introduced these pieces of switched-on DNA into mice. This allowed the team to further narrow the scope of their search until they had isolated a single piece of DNA that switched on the gene activity for developing hair follicles.

Further examining the DNA in that regulatory segment, the team found that it was just a single letter of genetic code that differed between people who have different hair colors.

The versions of this DNA associated with different hair colors were then each tested on the Kit ligand gene using cultured cells. The "blonde" switch reduced the activity of the gene by about 20%, which led the researchers to conclude they had identified a critical component of the DNA sequence.

Mice were then engineered to have a Kit ligand gene placed under either the genetic switches for blonde or brunette hair. Kingsley explains the results:

"Sure enough, when you look at them, that one base pair is enough to lighten the hair color of the animals, even though it is only a 20% difference in gene expression. This is a good example of how fine-tuned regulatory differences may be to produce different traits. The genetic mechanism that controls blonde hair doesn't alter the biology of any other part of the body. It's a good example of a trait that's skin deep - and only skin deep."

Their work with switching on different hair colors has led the team to suspect that the genome "is littered with switches." Kingsley thinks that the various activities of Kit ligand, as well as other genes, may be adjusted by very subtle DNA tweaks.

As well as leading to a better understanding of the molecular mechanisms involved in human diversity, Kingsley hopes that this work may lead to improving human resistance to many common diseases.

"The trick is," he says, is finding "which switches have changed to produce which traits."

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